A variety of polymers used for controlled release and deliver of drugs have been developed in the past 20 years. Most of the polymers are formed into implants or injectable microspheres. Such polymers are, and must be, biodegradable and biocompatible.
In order to form suitable forms of polymers, complicated fabrication processes are required which typically involve organic solvents. The use of organic solvents, however, may cause denaturation of some protein drugs and even traces of an organic solvent may be toxic.
Polymer hydrogels have been explored for drug delivery and controlled release. For example, chemically cross-linked polymer hydrogels have been used as implants. Some injectable drug delivery systems form chemically cross-led hydrogels in the body after injection. However, the chemical reactions occurring in The body may cause tissue irritation and damage.
In situ formed hydrogels from thermosensitive block copolymers have also been proposed as sustained release matrix for drugs. They have the advantage that there is no chemical reaction involved in the gel formation. These copolymer hydrogels are usually designed for macromolecular drugs such as protein and hormone drugs. The disadvantage of such temperature sensitive hydrogels is the practicality of using such a gel in injection.
In 1994, June Li and co-workers reported the formation of hydrogels between linear poly(ethylene glycol)s and cyclodextrin. However, since then, there has been few articles on injectable drug delivery systems. In recent years, S. W. Kim et al published a few papers on injectable drug delivery systems using thermosensitive or electrically sensitive hydrogels formed from biodegradable block copolymers.
The article describes poly(ethylene glycol)s (PEG) of high molecular weight which was found to form complexes with alpha-cyclodextrin (alpha-CD) in aqueous solutions to give gels in a wide range of concentration. The time of gelation decreased with increase in alpha-CD and PEG concentration, indicating that the gal formed during complex formation between alpha-CD chains. The time of gelation increases in the molecular weight of PEG, indicating that the PEG chains penetrate alpha CD cavities from the ends of PEG and are included in alpha CDS. X-Ray powder diffraction studies showed that the gel consists of both complexed alpha-CD and uncomplexed alpha CD, indicating partial inclusion of PEG chains by alpha-CD. Further, the gel-melting temperature increased with increases in PEG molecular weight and alpha-CD concentration, and decreased with increase in PEG concentrations, suggesting that gelation results from the formation of longer or shorter domains of alpha-CD-PEG inclusion complexes respectively. (Li J, Harada A Kamachi M., Sol-Gel Transition During Inclusion Complex-Formation between Alpha-Cyclodextrin and High Molecular-Weight Poly(ethylene glycol)s in Aqueous Solution. Polymer Journal 26:(9) 1019-1026 1994.
A further article explores polymers as potential drug delivery systems that display a physicochemical response to stimuli. Stimuli studied to date include chemical substances and changes in temperature, pH, and electric field. Homopolymer or copolymers of N-isopropylacrylamide and poly(ethylene oxide)poly(propylene oxide)-poly(ethylene oxide) are typical examples of thermosensitive polymers, but their use in drug delivery is problematic because they are toxic and nonbiodegradable.
Biodegradable polymers used for drug delivery to date have mostly been in the form of injectable microspheres or implant systems, which require complicated fabrication processes using organic solvents. Such systems have the disadvantage that the use of organic solvents can cause denaturation when protein drugs are to be encapsulated. Furthermore, the solid form requires surgical insertion, which often results in tissue irritation and damage, Thermosensitive, biodegradable hydrogels may be synthesized using blocks of poly(ethylene oxide) and poly(L-lactic acid). Aqueous solutions of these copolymers form a sol around 45° C. In this form, the polymer is injectable. On subsequent rapid cooling to body temperature, the loaded copolymer forms a gel that act as a sustained release matrix for drugs. (Jeong B, Bae Y H, Lee D S, Kim S W Biodegradable Block Copolymers as Drug Delivery Systems Nature 388:(6645) 860-862 Aug. 28, 1997.)
Another article (Kwon I C, Bac Y H, Kim S W, Electrically Erodible Polymer Gel for Controlled Release of Drugs Nature 354:(6351) 291-293 Nov. 28, 1991) is directed to new controlled drug-delivery systems being explored to overcome the disadvantages of conventional dosage forms. For example, stimulated drug delivery has been used to overcome the tolerance problems that occur with a constant delivery rate, to mimic the physiological pattern of hormonal concentration, and to supply drugs on demand. Stimuli sensitive polymers, which are potentially useful for pulsed drug delivery, experience changes in either their structure or their chemical properties in response to change in environmental conditions. Environmental stimuli include temperature, pH, light (ultraviolet or visible), electric field or certain chemicals. Volume changes of stimuli sensitive gel networks are particularly responsive to external stimuli, but swelling is slow to occur. Such systems also provide insight into intermolecular interactions. The polymeric system rapidly changes from a solid state to solution in response to small electric currents, by disintegration of the solid polymer complex into water-soluble polymers. The modulated release of insulin, and by extension other macromolecules, can be achieved with this polymeric system.
It is desired to have an improved hydrogel system for the delivery and controlled release of drugs into the body. It is desired that the process of forming the hydrogel be simple and easy. It is also desired that the properties of the hydrogels be tunable with different copolymers thus allowing delivery and controlled release of a variety of drugs, including protein drugs, and vaccines.